p120 catenin is required for normal renal tubulogenesis and glomerulogenesis

Department of Medicine, University of California, San Francisco, CA 94158, USA.
Development (Impact Factor: 6.46). 05/2011; 138(10):2099-109. DOI: 10.1242/dev.056564
Source: PubMed


Defects in the development or maintenance of tubule diameter correlate with polycystic kidney disease. Here, we report that absence of the cadherin regulator p120 catenin (p120ctn) from the renal mesenchyme prior to tubule formation leads to decreased cadherin levels with abnormal morphologies of early tubule structures and developing glomeruli. In addition, mutant mice develop cystic kidney disease, with markedly increased tubule diameter and cellular proliferation, and detached luminal cells only in proximal tubules. The p120ctn homolog Arvcf is specifically absent from embryonic proximal tubules, consistent with the specificity of the proximal tubular phenotype. p120ctn knockdown in renal epithelial cells in 3D culture results in a similar cystic phenotype with reduced levels of E-cadherin and active RhoA. We find that E-cadherin knockdown, but not RhoA inhibition, phenocopies p120ctn knockdown. Taken together, our data show that p120ctn is required for early tubule and glomerular morphogenesis, as well as control of luminal diameter, probably through regulation of cadherins.

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    • "Vertebrate p120 function has been extensively studied in conditional KO mice(Davis and Reynolds, 2006; Kurley et al., 2012 2012cs; Marciano et al., 2011; Perez-Moreno et al., 2006; Smalley-Freed et al., 2010). "
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    ABSTRACT: In vertebrate epithelia, p120-catenin mediates E-cadherin stability and suppression of RhoA. Genetic ablation of p120 in various epithelial tissues typically causes striking alterations in tissue function and morphology. Although these effects could very well involve p120's activity towards Rho, ascertaining the impact of this relationship has been complicated by the fact that p120 is also required for cell-cell adhesion. Here, we have molecularly uncoupled p120's cadherin stabilizing- and RhoA-suppressing activity. Unexpectedly, removing p120's Rho-suppressing activity dramatically disrupted the integrity of the apical surface, irrespective of E-cadherin stability. The physical defect was tracked to excessive actomyosin contractility along the vertical axis of lateral membranes. Thus, we suggest that p120's distinct activities toward E-cadherin and Rho are molecularly and functionally coupled, and this in turn enables the maintenance of cell shape in the larger context of an epithelial monolayer. Importantly, local suppression of contractility by cadherin-bound p120 appears to go beyond regulating cell shape, as loss of this activity also leads to major defects in epithelial lumenogenesis.
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    • "The biological interplay between p120 catenin and its family members is incompletely understood, especially during development. A number of studies have revealed critical yet diverse roles for p120 catenin in different organ systems (Bartlett et al., 2010; Davis and Reynolds, 2006; Elia et al., 2006; Kurley et al., 2012; Marciano et al., 2011; Oas et al., 2010; Perez-Moreno et al., 2006, 2008; Schackmann et al., 2013; Smalley-Freed et al., 2010; Smalley-Freed et al., 2011; Stairs et al., 2011; Tian et al., 2012). In p120 catenin conditional deletion studies, the results are highly tissue-specific and unpredictable. "
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    ABSTRACT: The intracellular protein p120 catenin aids in maintenance of cell-cell adhesion by regulating E-cadherin stability in epithelial cells. In an effort to understand the biology of p120 catenin in pancreas development, we ablated p120 catenin in mouse pancreatic progenitor cells, which resulted in deletion of p120 catenin in all epithelial lineages of the developing mouse pancreas: islet, acinar, centroacinar, and ductal. Loss of p120 catenin resulted in formation of dilated epithelial tubules, expansion of ductal epithelia, loss of acinar cells, and the induction of pancreatic inflammation. Aberrant branching morphogenesis and tubulogenesis were also observed. Throughout development, the phenotype became more severe, ultimately resulting in an abnormal pancreas comprised primarily of duct-like epithelium expressing early progenitor markers. In pancreatic tissue lacking p120 catenin, overall epithelial architecture remained intact; however, actin cytoskeleton organization was disrupted, an observation associated with increased cytoplasmic PKCζ. Although we observed reduced expression of adherens junction proteins E-cadherin, β-catenin, and α-catenin, p120 catenin family members p0071, ARVCF, and δ-catenin remained present at cell membranes in homozygous p120(f/f) pancreases, potentially providing stability for maintenance of epithelial integrity during development. Adult mice homozygous for deletion of p120 catenin displayed dilated main pancreatic ducts, chronic pancreatitis, acinar to ductal metaplasia (ADM), and mucinous metaplasia that resembles PanIN1a. Taken together, our data demonstrate an essential role for p120 catenin in pancreas development. Copyright © 2014. Published by Elsevier Inc.
    Developmental Biology 12/2014; 399(1). DOI:10.1016/j.ydbio.2014.12.010 · 3.55 Impact Factor
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    • "Phenotypes associated with p120 ablation in vivo appear to be largely tissue dependent and surprisingly unpredictable (Bartlett et al., 2010; Davis and Reynolds, 2006; Elia et al., 2006; Marciano et al., 2011; Oas et al., 2010; Perez-Moreno et al., 2006; Smalley- Freed et al., 2010; Stairs et al., 2011). For example, in the developing salivary gland, p120 ablation completely blocks acini formation (Davis and Reynolds, 2006). "
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    ABSTRACT: Although p120-catenin (p120) is crucial for E-cadherin function, ablation experiments in epithelial tissues from different organ systems reveal markedly different effects. Here, we examine for the first time the consequences of p120 knockout during mouse mammary gland development. An MMTV-Cre driver was used to target knockout to the epithelium at the onset of puberty. p120 ablation was detected in approximately one-quarter of the nascent epithelium at the forth week post-partum. However, p120 null cells were essentially nonadherent, excluded from the process of terminal end bud (TEB) morphogenesis and lost altogether by week six. This elimination process caused a delay in TEB outgrowth, after which the gland developed normally from cells that had retained p120. Mechanistic studies in vitro indicate that TEB dysfunction is likely to stem from striking E-cadherin loss, failure of cell-cell adhesion and near total exclusion from the collective migration process. Our findings reveal an essential role for p120 in mammary morphogenesis.
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